Most odors are composed of a mixture of many different molecules. Our overall objective is to study the physiological mechanisms by which the first olfactory processing structure, the olfactory bulb, refines complex odor signals, using electrophysiological and calcium imaging methods in rodent olfactory bulb slices, along with electron microscopic methods. Our focus is on synaptic mechanisms that operate within glomeruli, which are structures that act as both the site of input into the bulb from olfactory receptor neurons (ORNs) in the nose and also the starting point for output signals that pass onto the olfactory cortex. These output signals are carried by mitral cells (MCs). Studies in the three Specific Aims together will test the hypothesis that a small microcircuit of neurons that surround each glomerulus, involving excitatory external tufted (ET) cells and inhibitory periglomerular (PG) cells, dictates whether any particular odor signal passes onto the cortex in the form of MC action potentials. These studies of excitatory mechanisms in the glomerulus in the first two Aims will serve as the basis for experiments in Aim 3 that examine how inhibitory PG cells interact with excitation to suppress MC activation. Selective suppression of weak signals by the ET-PG cell microcircuit could enhance perceptual differences between similar odors and facilitate odor discrimination. Our experiments, studying basic mechanisms of odor discrimination, could also serve as the basis for understanding olfactory deficits associated with many neurological disorders in humans, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. All of these diseases are known to cause structural changes in the bulb, and our studies showing how certain key elements of the bulb circuit are involved in circuit level processing, will provide the foundation for linking disease-associated structural changes to olfactory dysfunction. PUBLIC HEALTH RELEVANCE: In humans, dysfunctions in the sense of smell are encountered in many neurological disorders such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Our studies of the basic mechanisms of information processing in the olfactory bulb will provide the basis for understanding specific disease- associated olfactory deficits and also potential treatments.